Department of Neurology, University of Ulm, Ulm, Germany.
Institute for Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany.
JAMA Neurol. 2018 May 1;75(5):600-607. doi: 10.1001/jamaneurol.2017.5129.
Knowledge about the metabolic states of patients with amyotrophic lateral sclerosis (ALS) may provide a therapeutic approach.
To investigate the association between the onset and prognosis of ALS and serum retinol-binding protein 4 (RBP4) concentration as a biomarker for insulin resistance and vitamin A metabolism.
DESIGN, SETTING, AND PARTICIPANTS: Case-control design for risk factors of ALS; cohort design for prognostic factors within ALS cases. Between October 1, 2010, and June 30, 2014, a population-based case-control study with randomly selected controls was established based on the ALS Registry Swabia in southern Germany, with a target population of 8.4 million inhabitants. Response rates were 64.8% among the cases and 18.7% among the controls. The dates of analysis were April 2016 to May 2017.
Serum samples were measured for RBP4. Information on covariates was assessed by an interview-based standardized questionnaire. Main outcomes and measures were adjusted odds ratios for risk of ALS associated with serum RBP4 concentration, as well as time to death associated with RBP4 concentration at baseline in ALS cases only. Conditional logistic regression was applied to calculate multivariable odds ratios for risk of ALS. Survival models were used in cases only to appraise their prognostic value.
Data from 289 patients with ALS (mean [SD] age, 65.7 [10.5] years; 172 [59.5%] male) and 504 controls (mean [SD] age, 66.3 [9.8] years; 299 [59.3%] male) were included in the case-control study. Compared with controls, ALS cases were characterized by lower body mass index, less educational attainment, smoking, light occupational work intensity, and self-reported diabetes. The median serum RBP4 concentration was lower in ALS cases than in controls (54.0 vs 59.5 mg/L). In the multivariable model, increasing RBP4 concentration was associated with reduced odds for ALS (top vs bottom quartile odds ratio, 0.36; 95% CI, 0.22-0.59; P for trend <.001), which persisted after further adjustment for renal function and for leptin and adiponectin. Among 279 ALS cases during a median follow-up of 14.5 months, 104 died (mean [SD] age, 68.9 [10.3] years; 56 [53.9%] male). In this ALS cohort, an inverse association was found between serum RBP4 concentration as a continuous measure and survival.
RBP4 was inversely related to risk for and prognosis of ALS, suggesting that vitamin A metabolism or impaired insulin signaling could be involved. Further research, including a prospective design and other biological markers, is necessary to clarify the role of insulin resistance in the pathogenesis of ALS.
重要性：了解肌萎缩侧索硬化症（ALS）患者的代谢状态可能为治疗提供一种方法。
目的：研究 ALS 的发病和预后与血清视黄醇结合蛋白 4（RBP4）浓度作为胰岛素抵抗和维生素 A 代谢生物标志物之间的关系。
设计、设置和参与者：2010 年 10 月 1 日至 2014 年 6 月 30 日，在德国南部的 Swabia 进行了基于人群的 ALS 病例对照研究设计，随机选择对照者作为 ALS 风险因素，ALS 病例中进行预后因素的队列设计，目标人群为 840 万居民。病例组的回应率为 64.8%，对照组的回应率为 18.7%。分析日期为 2016 年 4 月至 2017 年 5 月。
主要结果和测量：测量了 RBP4 血清样本。通过基于访谈的标准化问卷评估了协变量的信息。主要结果和测量指标是与 RBP4 浓度相关的 ALS 风险的调整比值比，以及仅在 ALS 病例中基线时 RBP4 浓度与死亡时间的相关性。应用条件逻辑回归计算 ALS 风险的多变量比值比。仅在病例中使用生存模型来评估其预后价值。
结果：289 名 ALS 患者（平均[标准差]年龄 65.7[10.5]岁；172[59.5%]男性）和 504 名对照者（平均[标准差]年龄 66.3[9.8]岁；299[59.3%]男性）纳入病例对照研究。与对照组相比，ALS 病例的特征是体重指数较低、教育程度较低、吸烟、轻度职业劳动强度和自报糖尿病。ALS 病例的中位血清 RBP4 浓度低于对照组（54.0 与 59.5mg/L）。在多变量模型中，RBP4 浓度的升高与 ALS 的发病几率降低相关（最高与最低四分位数比值比，0.36；95%CI，0.22-0.59；趋势 P<.001），即使进一步调整了肾功能、瘦素和脂联素也如此。在中位随访 14.5 个月的 279 名 ALS 病例中，有 104 人死亡（平均[标准差]年龄 68.9[10.3]岁；56[53.9%]男性）。在这个 ALS 队列中，血清 RBP4 浓度作为连续测量值与生存率呈负相关。
结论和相关性：RBP4 与 ALS 的发病和预后呈负相关，表明维生素 A 代谢或胰岛素信号转导受损可能参与其中。需要进一步的研究，包括前瞻性设计和其他生物标志物，以阐明胰岛素抵抗在 ALS 发病机制中的作用。
